Sulphonamide derivatives, process for their preparation, and their use as medicaments

ABSTRACT

Novel sulphonamide derivatives having CNS activity, processes for their preparation and their use as medicaments are disclosed. The present compounds are of formula (I) or a salt thereof:                    
     wherein: 
     P is benzothiophene, benzothiadiazole, quinoline, benzofuran or indole; 
     A is a single bond, a C 1-6 alkylene or a C 2-6 alkenylene group; 
     R 1  is halogen, C 1-6 alkyl optionally substituted by one or more halogen atoms, C 3-6 cycloalkyl, COC 1-6 alkyl, C 1-6 alkoxy, OCF 3 , hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, nitro, amino, C 1-6 alkylamino or C 1-6 dialkylamino, cyano or R 1  is phenyl, naphthyl; 
     n is 0, 1, 2, 3, 4, 5 or 6: 
     R 2  is hydrogen, C 1-6  alkyl or aryl C 1-6  alkyl or R 2  is linked to R 3  to form a group (CH 2 ) 2  or CH 2 ) 3 ; 
     R 3  is a group R 5  or together with R 5  forms a group (CH 2 ) 2 O or (CH 2 ) 3 O or R 3  is linked to R 2  to form a group (CH 2 ) 2  or (CH 2 ) 3 ; 
     R 4  is an N-piperazine ring optionally substituted by C 1-6 alkyl; and 
     R 5  is hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, COC 1-6 alkyl, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, nitro, trifluoromethyl, cyano or aryl.

This is a divisional of application Ser. No. 09/643,200 filed Aug. 21,2000 now U.S. Pat. No. 6,423,717B1 which is a continuation ofapplication Ser. No. 09/331,378 filed Jun. 18, 1999 now abandoned, whichis a 371 of PCT/EP97/07159, filed Dec. 15, 1997.

This invention relates to compounds having pharmacological activity,processes for their preparation, to compositions containing them and totheir use in the treatment of CNS disorders.

EPA 0 021 580 and EPA 0 076 072 describe sulphonamide derivatives whichare disclosed as having antiarrhythmic activity. A structurally distinctclass of compounds has now been discovered, which have been found tohave 5HT₆ receptor antagonist activity. 5HT₆ receptor antagonists arebelieved to be of potential use in the treatment of certain CNSdisorders such as anxiety, depression, epilepsy, obsessive compulsivedisorders, migraine, cognitive memory enhancement e.g. for the treatmentAlzheimers disease, sleep disorders, feeding disorders such as anorexiaand bulimia, panic attacks, withdrawal from drug abuse such as cocaine,ethanol, nicotine and benzodiazepines, schizophrenia, and also disordersassociated with spinal trauma and/or head injury such as hydrocephalus.Compounds of the invention are also expected to be of use in thetreatment of certain GI (gastrointestinal) disorders such as IBS(Irritable Bowel Syndrome).

The present invention therefore provides, in a first aspect, a compoundof formula (I) or a salt thereof:

wherein:

P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to7-membered heterocyclic ring each containing 1 to 4 heteroatoms selectedfrom oxygen, nitrogen or sulphur;

A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group;

R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more halogenatoms, C₃₋₆cycloalkyl, COC₁₋₆alkyl, C₁₋₆alkoxy, OCF₃, hydroxy,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl,nitro, amino, C₁₋₆alkylamino or diC₁₋₆alkylamino, cyano or R¹ is phenyl,naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-memberedheterocyclic ring each containing 1 to 4 heteroatoms selected fromoxygen, nitrogen or sulphur;

n is 0, 1, 2, 3, 4, 5 or 6,

R² is hydrogen, C₁₋₆ alkyl or aryl C₁₋₆ alkyl;

R³ is a group R⁵ or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃O orR³ is linked to R² to form a group (CH₂)₂ or (CH₂)₃;

R⁴ is —X(CH₂)_(p)—R⁶ where X is a single bond, CH₂, O, NH or N—C₁₋₆alkyl and p is 0 to 6 and R⁶ is an optionally substituted 5- to7-membered heterocyclic ring containing 1 to 3 heteroatoms selected fromnitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ areindependently hydrogen, C₁₋₆ alkyl or aryl C₁₋₆ alkyl; and

R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, COC₁₋₆alkyl,C₁₋₆alkoxy, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆ alkanoyl, nitro, trifluoromethyl, cyano oraryl.

C₁₋₆Alkyl groups, whether alone or as part of another group, may bestraight chain or branched. Preferred alkyl groups are generally methyland ethyl. As used herein the term aryl includes optionally substitutedphenyl and naphthyl.

When P is a bicyclic heterocyclic ring suitable examples includebenzothiophene, quinoline or isoquinoline. When P is a 5 to 7-memberedheterocyclic ring suitable examples include thienyl, furyl, pyrrolyl,triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyland pyrazinyl. The heterocyclic rings can be linked to the remainder ofthe molecule via any suitable carbon atom or, when present, a nitrogenatom. Suitable substituents for these rings include R⁵ groups as definedabove.

Preferably P is phenyl, thiophene, benzothiophene or naphthyl.Preferably A is a single bond, an ethylene group or a —CH═CH— group.Most preferably A is a single bond.

When R¹ is a heterocyclic group suitable examples include those listedabove. Preferably R¹ is halogen or C₁₋₆alkyl optionally substituted byone or more halogen atoms, for example methyl or trifluoromethyl.

Preferably n is 0, 1, 2 or 3, particularly 1 or 2.

Suitably R² is hydrogen or C₁₋₆ alkyl. Preferably R² is hydrogen.

It will be appreciated that when R³/R⁵ groups are linked together thetwo groups must be attached to adjacent carbon atoms of the phenyl ring.Preferably R³ is a group R⁵, in particular hydrogen.

Preferably R⁴ is meta with respect to the sulphonamide linkage.Preferably X is a bond, p is 0 and R⁶ is an optionally substituted 5- to7-membered heterocyclic ring. The heterocyclic rings can be linked tothe remainder of the molecule via a carbon atom or, when present, anitrogen atom. Optional substituents for these rings, which can bepresent on carbon and/or nitrogen atoms, include C₁₋₆alkyl, inparticular methyl. More preferably R⁴ is N-piperazine optionallysubstituted by C₁₋₆alkyl, particularly unsubstituted piperazine.

Preferably R⁵ is C₁₋₆alkoxy, most preferably methoxy. Preferably R⁵ ispara with respect to the sulphonamide linkage.

A preferred meaning for P-A is benzo[b]thiophen-2-yl orbenzo[b]thiophen-3-yl optionally substituted by one or two R¹ groups,especially 5-chloro-3-methylbenzo[2]thiophen-2-yl.

Particular compounds of the invention include:

4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-5-(pyridin-2-yl)-2-thiophenesulfonamide,

2,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-thiophenesulfonamide,

4-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzylsulfonamide,

2-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-trans-styrenesulfonamide,

3,4-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-[2,1,3]benzothiadiazole-4-sulfonamide,

5-Chloro-N-[4methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-2-benzothiophenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methyl-5-nitrobenzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-trifluoromethylbenzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-trifluoromethylbenzenesulfonamide,

2,5-Dimethoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

4-Fluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Ethyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-tert-Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Isopropyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-tert-Amyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-trifluoromethoxybenzenesulfonamide,

4-n-Butoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide,

5-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naphthalenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-naphthalenesulfonamide,

5-(Dimethylamino)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naphthalenesulfonamide,

4-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]-benzenesulfonamide,

4-Methoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-n-Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Amino-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

2-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

2,3,4-Trichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2,5-dimethylbenzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzenesulfonamide,

2,5-Dibromo-3,6-difluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2,3,5,6-tetramethylbenzenesulfonamide,

5-Chloro-2-methoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

3-Fluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3,4-Difluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-nitrobenzenesulfonamide,

3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methylbenzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-8-quinolinesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-phenylbenzenesulfonamide,

3,4-Dimethoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3,5-dimethyl-4-isoxazolesulfonamide,

4-Bromo-N-[4-methoxy-3-(4-ethylpiperazin-1-yl)phenyl]benzenesulfonamide,

2,3-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,

5-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methylbenzenesulfonamide,

3-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,

3-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide,

5-Chloronaphthalene-2-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

5-Chloronaphthalene-1-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

4-Chloronaphthalene-1-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

7-Chloronaphthalene-1-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

5-Chloro-2-methylbenzo[b]thiophene-3-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

Benzofuran-2-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

1-Methyl-1H-indole-2-sulfonicacid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

5-Pyridin-2-ylthiophene-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

N-(4-Methoxy-3-piperazin-1-ylphenyl)-3-trifluoromethylbenzenesulfonamide,

3-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

3,5-Dimethylisoxazole-4-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

3,5-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

2,5-Dibromo-3,6-difluoro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

Naphthalene-1-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide,

2-Bromo-5-chlorothiophene-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

2-Chloro4-fluoro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

3-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

5-Chloronaphthalene-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

4-Bromo-5-chlorothiophene-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

2,5-Dichlorothiophene-3-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide

4-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

5-Chloro-2-methylbenzo[b]thiophene-3-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

1-Methyl-1H-indole-2-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

Benzofuran-2-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide,

Naphthalene-2-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide,

5-Chloronaphthalene-1-sulfonicacid(4-methoxy-3-piperazin-1-ylphenyl)amide,

4-Chloro-2,5-dimethyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

3,4-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-4-methylbenzenesulfonamide,

2-Trifluoromethyl-N-(4-methoxy-3-piperazin-1ylphenyl)benzenesulfonamide,

4-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

4-tert-Butyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide,

Naphthalene-1-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

Thiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

5-Chlorothiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

5-Pyridin-2-ylthiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

2,5-Dichlorothiophene-3-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

4-Bromo-5-chlorothiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

3-Bromo-5-chlorothiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

4-Chloro-2,5-dimethyl-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide,

Naphthalene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide.

3-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide,

3,5-Dichloro-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide,

4-tert-Butyl-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide,

2,5-Dibromo-3,6-difluoro-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide,

2,5-Dibromo-3,6-difluoro-N-(7-piperazin-1-yl-2,3-dihydrobenzofuran-5-yl)benzenesulfonamide,

4-Chloro-2,5-dimethyl-N-(7-piperazin-1-yl-2,3-dihydrobenzofuran-5-yl)benzenesulfonamide,

5-Chloro-3-methyl benzo[b]thiophene-2-sulphonicacid[3-(4-cyclopropylmethylpiperazin-1-yl)-4-methoxy-phenyl]amide,

5-Chloro-3-methyl benzo[b]thiophene-2-sulphonicacid[3-(4-benzylpiperazin-1-yl)-4-methoxy-phenyl]-amide,

5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-hydroxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide,

5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-benzyloxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide,

5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-ethoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide,

5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-isopropoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide,

5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-methoxy-3-(1-methylpyrrolidin-3-yloxy)-phenyl]-amide,

Naphthalene-2-sulfonicacid[2-bromo-5-(4-methylpiperazin-1-yl)phenyl]amide

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-chloro-3-(4-methylpiperazin-1-yl)phenyl]amide,

Naphthalene-2-sulfonicacid[4-bromo-3-(4-methylpiperazin-1-yl)phenyl]amide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[3-(2-dimethylaminoethoxy)-4-iodophenyl]amide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-yl]amide,

1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole,

1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenyl]amide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[2-(2-hydroxyethyl)-4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide,

1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indolehydrochloride,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amide,

4-Bromo-N-[4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]benzenesulfonamide,

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amide

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-3-(1-methylpiperidinyl)phenyl]amide

Naphthalene-2-sulfonic acid[3-(4-methylpiperazin-1-yl)phenyl]amide andpharmaceutically acceptable salts thereof

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form solvates such as hydrates, andthe invention also extends to these forms. When referred to herein, itis understood that the term ‘compound of formula (I)’ also includesthese forms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including diastereomers and enantiomers and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises the coupling of a compound of formula (II):

in which R¹, n, P, and A are as defined in formula (I) or protectedderivatives thereof and L is a leaving group with a compound of formula(III):

in which R², R³, R⁴ and R⁵ are as defined in formula (I) or protectedderivatives thereof and optionally thereafter:

removing any protecting groups,

forming a pharmaceutically acceptable salt.

Suitable leaving groups include halogen, in particular chloro. Thereaction of a compounds of formulae (II) and (III) is carried out bymixing the two reagents together, optionally in an inert solvent such asacetone. Such a reaction may be carried out in the presence of base.

Those skilled in the art will appreciate that it may be necesary toprotect certain groups. Suitable protecting groups and methods for theirattachment and removal are conventional in the art of organic chemistry,such as those described in Greene T. W. ‘Protective groups in organicsynthesis’ New York, Wiley (1981). For example, suitable protectinggroups for the piperazine group include BOC, COCCl₃, COCF₃ and methylthe latter of which may be removed by treatment with 1-chloroethylchloroformate according to standard procedures.

N-substituted piperazines can be prepared by acylation or alkylation ofthe appropriate NH-piperazine compound according to standard procedures.

Compounds of formulae (II) and (III) are commercially available or maybe prepared according to known methods or analogous to known methods.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable saltshave 5HT₆ receptor antagonist activity and are believed to be ofpotential use in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, migraine,Alzheimers disease (cognitive memory enhancement), sleep disorders(including disturbances of Circadian Rythym), feeding disorders such asanorexia and bulimia, panic attacks, withdrawal from drug abuse such ascocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and alsodisorders associated with spinal trauma and/or head injury such ashydrocephalus. Compounds of the invention are also expected to be of usein the treatment of certain GI disorders such as IBS

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment or prophylaxis of theabove disorders.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unitdoses may be administered more than once a day, for example two or threea day, so that the total daily dosage is in the range of about 0.5 to100 mg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1 1-(2-Methoxy-5-nitrophenyl)piperazine (D1)

A solution of 5M sulphuric acid (114 ml) was added over 0.3 h to1-(2-methoxyphenyl)piperazine (110 g) at 0° C. with stirring. To theice-cooled stirred slurry was then added, over 1.75 h, concentratedsulphuric acid (560 ml) and the temperature was maintained for a further1.5 h. Potassium nitrate (71.5 g) was then added portionwise over 1.5 hto the stirred, cold, viscous mixture which was then left to stand for18 h. The solution was poured onto ice (2 Kg) and the resulting cooledmixture brought to pH 12 by the addition of 40% sodium hydroxidesolution. The oily mixture was extracted with ethyl acetate (2×2L) andthe combined organic extracts were washed with water (3L), dried(Na₂SO₄), concentrated to a residue which was stirred with diethyl ether(700 ml) to give the title compound (D1) as a yellow solid, m.p. 84-87°C. (95 g, 70%). MH⁺238.

Description 24-tert-Butoxycarbonyl-1-(2-methoxy-5-nitrophenyl)piperazine (D2)

To a stirred heterogeneous solution of1-(2-methoxy-5-nitrophenyl)piperazine (D1) (99.2 g) in tetrahydrofuran(1.1L) and water (1.1L) was added a solution of di-tert-butyldicarbonate(91.3 g) in tetrahydrofuran (300 ml) over 0.5 h. Potassium carbonate(60.7 g) was then added in portions over 0.5 h and the mixture wasstirred at ambient temperature for 18 h. The whole was concentrated toremove the organic solvent and the resulting mixture was extracted withdichloromethane (2×1L). The combined organic phases were washed withwater (1L), dried (Na₂SO₄) and concentrated to a residue which wasstirred with diethyl ether (500 ml) and hexane (750 ml) to afford thetitle compound (D2)as a yellow solid, m.p. 136-7° C. (125 g, 89%).MH⁺338.

Description 34-tert-Butoxycarbonyl-1-(5-amino-2-methoxyphenyl)piperazine (D3)

A slurry of 10% palladium on carbon (10 g) in a solution of4-tert-butoxycarbonyl-1-(2-methoxy-5-nitrophenyl)piperazine (D2) (124.5g) in ethanol (3.5L) and water (50 ml) was stirred with hydrogen atambient temperature and atmospheric pressure for 18 h. The reactionmixture was filtered and the filtrate concentrated to afford the titlecompound (D3) as a gum (112 g, 99%). MH⁺ 308.

Description 4-14 General Preparation ofN-[4-methoxy-3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]arylsulfonaindes(D4-D14)

A solution of 4t-butoxycarbonyl-1-(5-amino-2-methoxyphenyl)piperazine(D3) (15.6 mmol), diisopropylethylamine (15.6 mmol) and the appropriatearyl sulfonyl chloride (15.6 mmol) in dichloromethane (100 ml) wasstirred at room temperature for 18 h. The mixture was concentrated andthe residue chromatographed on silica gel eluting with adichloromethanelmethanol gradient to give the following pure titleproducts.

MS(MH⁺) 2-Chloro-4-fluoro-N-[4-methoxy-3-(4-t-butoxy- *carbonyl-1-piperazinyl)phenyl]benzenesulfonamide (D4)3-Bromo-N-[4-methoxy-3-(4-t-butoxycarbonyl-1- *piperazinyl)phenyl]benzenesulfonamide (D5)3-Chloro-N-[4-methoxy-3-(4-t-butoxycarbonyl-1- *piperazinyl)phenyl]benzenesulfonamide (D6)4-Bromo-5-chlorothiophene-2-sulfonic acid[4- *methoxy-3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]- amide (D7)2,5-Dichlorothiophene-3-sulfonic acid[4- *methoxy-3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]- amide (D8)4-Bromo-N-[4-methoxy-3-(4-t-butoxycarbonyl-1- 526/528piperazinyl)phenyl]benzenesulfonamide (D9)5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic 552/554acid[4-methoxy-3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]- amide (D10)5-Chloro-2-methylbenzo[b]thiophene-3-sulfonic acid[4- 552/554methoxy-3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]- amide (D11)Benzofuran-2-sulfonic acid[4-methoxy-3-(4-t-butoxy- 488carbonyl-1-piperazinyl)phenyl]amide (D12) 1-Methyl-1H-indole-2-sulfonicacid[4-methoxy-3-(4-t-butoxy- 501 carbonyl-1-piperazinyl)phenyl]amide(D13) 5-Chloronaphthalene-2-sulfonic acid[4-methoxy- *3-(4-t-butoxycarbonyl-1-piperazinyl)phenyl]amide (D14) *Intermediateused crude without isolation

Description 10

5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid(4-methoxy-3-(4-tert-butoxycarbonylpiperazin-1phenyl)amide (D10)

Pyridine (60 ml) was added to a stirred solution of4-tert-butoxycarbonyl-1-(5-amino-2-methoxyphenyl)piperazine (D3) (112 g)in dichloromethane (1L) at ambient temperature under argon. To thissolution was added over 0.75 h a solution of5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (102.5 g) indichloromethane (2.1L) and the purple solution was stirred for 18 h. Themixture was then washed with 1M hydrochloric acid solution (3L), water(3L), dried (Na₂SO₄), and concentrated to a foam which was stirred withacetone (800 ml) and water (800 ml) to afford the title compound (D10)as a maroon solid, m.p. 100-103° C. (194.9 g, 97%). MH⁺ 552/554.

Description 15 1-(2-Methoxy-5-nitrophenyl)-4-trichloroacetylpiperazine(D15)

A solution of 5-nitro-1-(2-methoxyphenyl)piperazine (D1) (44 g) indichloromethane (300 ml) was added to a stirred solution oftrichloroacetylchloride (32 ml) in dichloromethane (200 ml) over 0.25 h.After 3 hrs, the reaction mixture was concentrated and the residuerecrystallised from chloroform to yield the title compound (D15) as ayellow solid (43 g, 61%). Found MH⁺ 382/384.

Description 16 1-(5-Amino-2-methoxyphenyl)-4trichloroacetylpiperazine(D16)

A solution of stannous chloride dihydrate (27 g) in concentrated HCl (60ml) was slowly added to a stirred suspension of1-(2-methoxy-5-nitrophenyl)-4-trichloroacetylpiperazine (D15) (15 g) inconcentrated HCl/ethanol (1:2, 120 ml). After 24 hrs, the mixture wasfiltered, diluted with dichloromethane (600 ml) and basified with Na₂CO₃solution. The layers were separated, the organic phase dried,concentrated to ⅓ the volume and acidified with 1M ethereal HCl solutionto afford the title compound (D16) as a green solid (2.5 g, 15%). FoundMH⁺ 352.

Description 17Cyclopropyl-[4-(2-methoxy-5-nitrophenyl)-piperazin-1-yl]methanone (D17)

To a solution of 1-(2-methoxy-5-nitrophenyl)-piperazine (500 mg, 2.1mmol) in dichloromethane (50 ml) at 0° C. under argon was addedtriethylamine (0.59 ml, 4.2 mmol) and cyclopropane carbonyl chloride(2.1 mmol). Stirring was continued for 12 hrs. The reaction mixture wasconcentrated in vacuo and partitioned between saturated aqueous NaHCO₃and dichloromethane. The organic layer was dried over sodium sulphateand concentrated in vacuo to give the title compound (D17) in 90% yield.Found MH⁺ 306.

Description 18 [4-(2-Methoxy-5-nitrophenyl)-piperazin-1-yl]phenylmethanone (D18)

The title compound was prepared in 85% yield using the procedureoutlined in D17 using benzoyl chloride. Found MH⁺342.

Description 19 [4-(5-Amino-2-methoxy-phenyl)-piperazin-1-yl]cyclopropylmethanone (D19)

A solution of thecyclopropyl-[4-(2-methoxy-5-nitrophenyl)-piperazin-1-yl]methanone (D17)(1.8 mmol) in ethanol was hydrogenated over 10% Palladium on charcoalcatalyst for 2 hrs at room temperature to give the title compound in 91%yield. Found MH⁺ 276.

Description 20 [4-(5-Amino-2-methoxy-phenyl)-piperazin-1-yl]phenylmethanone (D20)

The title compound was prepared in 95% yield using the procedureoutlined in D19. Found MH⁺ 312

Description 213-(4-Cyclopropylmethyl-piperazin-1-yl)-4-methoxy-phenylamine (D21)

To a solution of[4-(5-amino-2-methoxy-phenyl)-piperazin-1-yl]cyclopropyl methanone (D19)(1.6 mmol) in dry THF (10 ml) under argon was added LiAlH₄ (240 mg, 6.4mmol). The resulting mixture was heated to reflux for 12 hrs and cooledbefore quenching with water (0.25 ml), 10% aqueous NaOH (0.25 ml) andfinally water (0.75 ml). Filtration through celite and concentration invacuo afforded the title compound (D21) in 75% yield. Found MH⁺ 262.

Description 22 3-(4Benzyl-piperazin-1-yl)-4-methoxy-phenylamine (D22)

The title compound was prepared in 76% yield using the procedureoutlined in D21. Found MH⁺ 298.

Description 23 Methane sulphonic acid 1-methyl pyrrolidin-3-yl ester(D23)

To a solution of 1-methyl-pyrrolidin-3-ol (2.0 g, 20 mmol) andtriethylamine (3 ml, 22 mmol) in dichloromethane (25 ml) at 0° C. underargon was added methane sulphonyl chloride (2.4 g, 21 mmol). Stirringwas continued at 0° C. to room temperature for 1 hr before partitioningbetween saturated aqueous sodium bicarbonate and dichloromethane. Theorganic phase was dried over sodium sulphate and concentrated in vacuato afford the crude mesylate (3.6 g) which was used directly in the nextstep.

Description 24 3-(2-Methoxy-5-nitrophenoxy)-1-methyl-pyrrolidine (D24)

A solution of 2-methoxy-5-nitro phenol (5.1 g, 30 mmol) in DMF (10 ml)was added to sodium hydride (1.6 g, 66 mmol) under argon. After 1 hr asolution of the crude mesylate (D23, 3.6 g, 20 mmol) in DMF (10 ml) wasadded and the reaction mixture warmed to 50° C. for 48 hrs. The reactionwas cooled, quenched with water and concentrated in vacuo beforepartitioning between saturated aqueous sodium bicarbonate anddichloromethane. The organic phase was dried over sodium sulphate andconcentrated in vacuo. The residue was purified by chromatography onsilica gel to afford the title compound (D24). Found MH⁺ 253.

Description 25 4-Methoxy-3-(1-methyl-pyrrolidin-3-yloxy)phenylamine(D25)

A solution of 3-(2-methoxy-5-nitro-phenoxy)-1-methyl-pyrrolidine (3.0 g,0.12 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium oncharcoal catalyst for 2 hrs to afford the title compound (D25). FoundMH⁺ 223.

Description 26 1-(4-Bromo-3-nitrophenyl)-4-methylpiperazine (D26)

A solution of 1-methyl-4-(3-nitrophenyl)piperazine (EP0533267A) (1.0 g;4.5 mmol) in glacial acetic acid (25 ml) was treated with bromine (0.23ml; 1 equivalent). The reaction mixture was stirred at 75° overnight,then cooled, filtered, and the yellow sticky solid was partitionedbetween potassium carbonate (aq) and 2% methanol in dichloromethane. Theorganic phase was dried (Na₂SO₄) and evaporated under reduced pressureto leave the title compound (D26) as a viscous orange oil (928 mg, 68%)MH⁺=300/302.

Description 27 2-Bromo-5-(4-methylpiperazin-1-yl)phenylamine (D27)

A suspension of iron powder (1.77 g, 31.6 mmol) in saturated aqueousammonium chloride solution (140 ml) at 100° C., was treated dropwisewith a solution of 1-(4-bromo-3-nitrophenyl)-4-methylpiperazine (D26)(3.54 g, 11.8 mmol) in methanol (70 ml). The mixture was refluxed for afurther 1 h, and was then cooled and partitioned between water and 3%methanol in dichloromethane. The organic phase was dried (Na₂SO₄) andevaporated under reduced pressure to give the crude product. This waspurified by chromatography on silica gel, eluting with methanol anddichloromethane to give the title compound (D27) as a white solid (2.18g, 68%) MH⁺=270/272.

Description 28 2-Methoxy-6-methylphenylamine (D28)

A solution of 1-methoxy-3-methyl-2-nitrobenzene (15.04 g, 0.09 mol) inethanol (250 ml) was hydrogenated over 10% palladium on charcoal (4 g)at atmospheric pressure and at room temperature, for 18 h. The catalystwas removed by filtration, and the filtrate evaporated under reducedpressure to leave the title compound (D28) as an amber oil, whichcrystallised on standing (11.18 g, 91%).

¹H NMR (250 MHz, CDCl₃) δ (ppm): 6.75-6.65 (m, 3H), 3.81 (s, 3H), 3.72(br s, 2H), 2.19 (s, 3H).

Description 29 1-(2-Methoxy-6-methylphenyl)-4-methylpiperazine (D29)

A mixture of 2-methoxy-6-methylphenylamine (D28) (3.62 g, 26.4 mmol),mechlorethamine hydrochloride (12.7 g, 66 mmol) and potassium carbonate(15 g) in chlorobenzene (90 ml) was refluxed under argon for 20 h. Themixture was cooled and filtered, and the filtrate evaporated underreduced pressure to leave the title compound (D29) as a red oil whichslowly crystallised on standing (5.4 g, 93%) MH⁺=221.

Description 30 1-(6-Methoxy-2-methyl-3-nitrophenyl)-4-methylpiperazine(D30)

A solution of 1-(2-methoxy-6-methylphenyl)-4-methylpiperazine (D29) (6.2g, 28 mmol) in concentrated sulfuric acid (50 ml) was treatedportionwise with potassium nitrate (3.3 g, 33 mmol) over 5 mins,maintaining the temperature at 25-30° C. The mixture was stirredovernight at room temperature, then added to ice, and basified with 40%sodium hydroxide solution. The mixture was extracted withdichloromethane and the organic phase was dried (Na₂SO₄) and evaporatedunder reduced pressure to give crude compound. Purification bychromatography on silica gel eluting with methanol and dichloromethaneafforded the title compound (D30) (4.56 g, 61%) MH⁺=266.

Description 312-[3-Methoxy-2-(4-methylpiperazin-1-yl)-6-nitrophenyl]ethanol (D31)

A mixture of 1-(6-methoxy-2-methyl-3-nitrophenyl)-4-methylpiperazine(D30) (360 mg, 1.36 mmol), dry dimethylsulfoxide (3 ml),paraformaldehyde (82 mg, 2.72 mmol) and potassium tert-butoxide (52 mg,0.46 mmol) was heated at 70-75° C. for 30 h. After cooling, the mixturewas partitioned between water and ethyl acetate. The organic phase wasdried (Na₂SO₄) evaporated under reduced pressure and purified bychromatography on silica gel, eluting with methanol and dichloromethane,to give the title compound (D31) as a yellow solid (152 mg, 38%)MH⁺=296.

Description 322-[6-Amino-3-methoxy-2-(4-methylpiperazin-1-yl)phenyl]ethanol (D32)

The title compound (D32) was prepared from2-[3-methoxy-2-(4-methylpiperazin-1-yl)-6-nitrophenyl]ethanol (D31) (142mg, 0.48 mmol) using the method of Description 28 as a clear oil whichcrystallised on standing (94 mg, 74%) MH⁺=266.

Description 33 4-Methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenylamine(D33)

The title compound (D33) was prepared from1-(6-methoxy-2-methyl-3-nitrophenyl)-4-methylpiperazine (D30) (150 mg,0.56 mmol) using the method of Description 28 as a tan powder (78 mg,59%) MH⁺=236.

Description 34 1-(2-Methoxy-4-nitrophenyl)-4-methylpiperazine (D34)

A mixture of N-methylpiperazine (216 mg, 2.15 mmol),2-bromo-5-nitroanisole (1 g, 4.3 mmol), potassium carbonate (447 mg,3.23 mmol), copper (I) bromide (86.6 mg, 0.30 mmol) in pyridine (0.5 ml)and toluene (2 ml) was heated at 100° C. overnight. After cooling, themixture was partitioned between water and ether and the aqueous phasewas further extracted with ethyl acetate. The combined organic phaseswere dried (Na₂SO₄) and evaporated under reduced pressure, to give thecrude product. This was purified by chromatography on silica gel,eluting with methanol and dichloromethane, to give the title compound(D34) as a yellow/brown oil (80 mg, 15%) MH⁺=252.

Description 35 3-Methoxy-4-(4-methylpiperazin-1-yl)phenylamine (D35)

The title compound (D35) was prepared from1-(2-methoxy-4-nitrophenyl)-4-methylpiperazine (D34) (80 mg, 0.319 mmol)using the method of Description 28 (50 mg, 71%) MH⁺=222.

Description 36 4(2-Methoxy-5-nitrophenyl)pyridine (D36)

A stirred mixture of 2-bromo-4-nitroanisole (7.6 g, 32.7 mmol),4-pyridineboronic acid (4.07 g, 33 mmol) and powdered sodium carbonate(13.8 g, 5 equivalents) in 1:1 1,2-dimethoxyethane:water (1,360 ml) wasdegassed for 0.5 hr, by the passage of a stream of argon.Tetrakistriphenylphosphine palladium (0) (1.35 g) was added, and themixture was cooled, the solvents evaporated under reduced pressure toapproximately half-volume, and the aqueous residue was acidified with 5Nhydrochloric acid and washed with ethyl acetate. The acid phase was thenbasified with solid potassium carbonate, and extracted into ethylacetate, the organic phase was dried (Na₂SO₄) and evaporated underreduced pressure to give the title compound (D36) as a pale yellow solid(3.4 g, 45%).

¹H NMR (250 MHz, CDCl₃) δ (ppm): 8.7 (d, 2H), 8.32 (d, 1H), 8.29-8.25(m, 1H), 7.47 (d, 2H), 7.09 (d, 1H), 3.96 (s, 3H).

Description 374-(2-Methoxy-5-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (D37)

A solution of 4-(2-methoxy-5-nitrophenyl)pyridine (D36) (3.4 g, 14.8mmol) in acetone (150 ml) was treated with excess iodomethane (5 ml) andthe mixture stirred at room temperature overnight. The precipitatedquaternary salt was filtered off, washed with acetone and dried, giving5.02 g. This was dissolved in 1:1 ethanol:water (230 ml) and treatedportionwise at room temperature, under argon, with sodium borohydride(1.23 g, 32.4 mmol). The mixture was stirred for 1 h at room temperaturethen potassium carbonate (10 g) was added and the organic layer wasseparated from the aqueous phase, which was back-extracted with ethylacetate. The organic phases were combined and dried (Na₂SO₄) andevaporated under reduced pressure to give the title compound (D37) as anorange oil, which slowly crystallised (3.05 g, 91%).

¹H NMR (250 MHz, CDCl₃) δ (ppm): 8.15 (d, 1H), 8.05 (s, 1H), 6.9 (d,1H), 5.9-5.84 (m, 1H), 3.9 (s, 3H), 3.15-3.05 (m, 2H), 2.7-2.61 (m, 2H),2.6-2.5 (m, 2H), 2.4 (s, 3H).

Description 38 4-Methoxy-3-(1-methylpiperidin-1-yl)phenylamine (D38)

A solution of4-(2-methoxy-5-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (D37)(1.0 g, 4 mmol) in ethanol (50 ml) and glacial acetic acid (5 ml) washydrogenated over 10% palladium on charcoal at 50° C. and 50 psi for 4days. The catalyst was removed by filtration, the filtrate evaporatedunder reduced pressure and the residue partitioned between potassiumcarbonate (aq) and dichloromethane. The organic phase was dried (Na₂SO₄)and evaporated under reduced pressure to give the title compound (D38)as a brown oil which rapidly crystallised to a light tan powder (760 mg,86%). MH⁺=221.

Description 394-Methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylaminehydrochloride (D39)

A solution of4-(2-methoxy-5-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (D37)(570 mg, 2 mmol), in ethanol (35 ml), was warmed to 60° C. and treateddropwise with a solution of stannous chloride (2 g) in conc.hydrochloric acid (4 ml). The mixture was heated for a further 2 h afteraddition, and allowed to cool. The precipitate was filtered off, andwashed with ethanol to give the title compound (D39) as a pale yellowpowder (580 mg, 99%). MH⁺=219.

General Preparation ofaryl-N-(4-methoxy-3-piperazin-1-yl)-benzenesulfonamide Hydrochlorides onSolid Phase Description 40 Preparation of1-(2-methoxy-5-nitrophenyl)piperazin-4-yl bound to Merrifield resin

A solution of 1-(2-methoxy-5-nitrophenyl)piperazine (9.7 g) inN-methylpyrrolidin-2-one (NMP) (150 ml) was heated withchloromethylpolystyrene-divinylbenzene resin (Merrifield, 150-300 mesh)at 60° C. for 24 h under argon. The resin was then filtered, washed(NMP; dichloromethane/methanol gradient) and dried to give the titlecompound (6.9 g) which was used directly in Description 41.

Description 41 Preparation of 1-(5-amino-2-methoxyphenyl)piperazin-4-ylbound to Merrifield resin

A solution of stannous chloride dihydrate (9 g) in N,N-dimethylformamide(DMP) (120 ml) was stirred for 72 h at room temperature under argon withthe resin from Description 40 (6.9 g). The resin was filtered, washed(DMF; dichloromethane/methanol gradient) and dried to give the titlecompound (6.6 g) which was used directly in Description 42.

Description 42 General Preparation ofaryl-N-(4-methoxy-3-(4-polymerylpiperazin-1-yl)-benzenesulfonamide boundto Merrifield resin

A solution of aryl sulfonyl chloride (0.4 mmol) anddi-isopropylethylamine (1 mmol) in dichloromethane (3 ml) was agitatedfor 24 h at room temperature with the resin (0.1 mmol) from Description41. The resin was then filtered, washed (dichloromethane;dichloromethane/methanol gradient; methanol) to yield the title compoundwhich was used directly in Examples 133-137.

Description 43 (S)-1-Methyl-2-(2-methoxy-5-nitrophenoxy)-pyrrolidine(D43)

A solution of 2-methoxy-5-nitrophenol (5.58 g; 0.033 mol),(S)-1-methyl-2-hydroxymethylpyrrolidine (3.45 g; 0.03 mol) andtriphenylphosphine (8.65 g; 0.033 mol) in dry THF (80 ml) was cooled to50 and treated with DEAD (5.2 ml; 0.033 mol) over 15 min. The reactionmixture was allowed to stand at RT for 16 h, then evaporated in vacuoand partitioned 5% NaOH(aq)/Et2O. The organic phase was separated andextracted with 10% HCl(aq). The aqueous extract was washed with Et2O,basified with 40% NaOH(aq) and extracted with Et2O. The organic extractswere washed with H2O, dried over Na2SO4 and evaporated in vacuo to yieldthe title compound (D43) (6.79 g; 85%) MH⁺=267.

Description 44 (S)-1-Methyl-2-(2-methoxy-5-aminophenoxy)pyrrolidine D44)

A solution of (S)-1-methyl-2-(2-methoxy-5-nitrophenoxy)pyrrolidine (D43)(6.79 g;0.0255 mol) in ethanol (200 ml) was hydrogenated in the presenceof 5% Pd/C catalyst (0.5 g added as an aqueous slurry) at atmosphericpressure and RT for 16 hours. The catalyst was removed by filtrationthrough kieselguhr and the filtrate evaporated in vacuo to yield thetitle compound (D44) (5.64 g; 93%) MH⁺=237.

EXAMPLE 1N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]thiophene-2-ylsulfonamide

A solution of thiophene-2-sulfonyl chloride (82 mg;0.45 mmol) in acetone(2 ml) was added to a solution of4-methoxy-3-(4-methylpiperazin-1-yl)aniline (100 mg;0.45 mmol) inacetone (2 ml) and the mixture stood overnight at room temperature. Theresultant crystalline solid was filtered off and washed with acetone,then diethyl ether, to afford the title compound as the hydrochloridesalt. (153 mg;84%). MS: m/z=368.

MS (MH+) 4-Bromo-N-[4-methoxy-3-(4-methylpipera- 441zin-1-yl)phenyl]benzenesulfonamide (E2)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thio- 368phenesulfonamide (E3)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-5-(pyri- 445din-2-yl)-2-thiophenesulfonamide (E4)2,5-Dichloro-N-[4-methoxy-3-(4-methylpipera- 436/438zin-1-yl)phenyl]-3-thiophenesulfonamide (E5)4-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpipera- 482zin-1-yl)phenyl]-2-thiophenesulfonamide (E6)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene- 362 sulfonamide(E7) 3-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpipera- 480/482zin-1-yl)phenyl]-2-thiophenesulfonamide (E8)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzyl- 376 sulfonamide(E9) 2-Bromo-N-[4-methoxy-3-(4-methylpipera- 440/442zin-1-yl)phenyl]-benzenesulfonamide (E10)3-Bromo-N-[4-methoxy-3-(4-methylpipera- 440/442zin-1-yl)phenyl]-benzenesulfonamide (E11)3-Chloro-N-[4-methoxy-3-(4-methylpipera- 410zin-1-yl)phenyl]-4-methyl-benzenesulfonamide (E12)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-trans-sty- 388renesulfonamide (E13) 3,4-Dichloro-N-[4-methoxy-3-(4-methylpipera- 430zin-1-yl)phenyl]-benzenesulfonamide (E14)3,5-Dichloro-N-[4-methoxy-3-(4-methylpipera- 430/432zin-1-yl)phenyl]benzenesulfonamide (E15) N-[4-Methoxy-3-(4-methylpipera-420 zin-1-yl)phenyl]-[2,1,3]benzothiadiazol-4-sulfonamide (E16)5-Chloro-N-[4-methoxy-3-(4-methylpipera- 466zin-1-yl)phenyl]-3-methyl-2-benzothiophenesulfona- mide (E17)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-meth- 421yl-5-nitrobenzenesulfonamide (E18)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-tri- 430fluoromethylbenzenesulfonamide (E19)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-tri- 430fluoromethylbenzenesulfonamide (E20)2,5-Dimethoxy-N-[4-methoxy-3-(4-methylpipera- 422zin-1-yl)phenyl]-benzenesulfonamide (E21)4-Fluoro-N-[4-methoxy-3-(4-methylpipera- 380zin-1-yl)phenyl]benzenesulfonamide (E22)4-Chloro-N-[4-methoxy-3-(4-methylpipera- 396zin-1-yl)phenyl]benzenesulfonamide (E23)4-Iodo-N-[4-methoxy-3-(4-methylpipera- 488zin-1-yl)phenyl]benzenesulfonamide (E24)4-Ethyl-N-[4-methoxy-3-(4-methylpipera- 390zin-1-yl)phenyl]benzenesulfonamide (E25)4-tert-Butyl-N-[4-methoxy-3-(4-methylpipera- 418zin-1-yl)phenyl]-benzenesulfonamide (E26)4-Iospropyl-N-[4-methoxy-3-(4-methylpipera- 404zin-1-yl)phenyl]benzenesulfonamide (E27)4-tert-Amyl-N-[4-methoxy-3-(4-methylpipera- 432zin-1-yl)phenyl]benzenesulfonamide (E28)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-tri- 446fluoromethoxy-benzenesulfonamide (E29)4-n-Butoxy-N-[4-methoxy-3-(4-methylpipera- 434zin-1-yl)phenyl]benzenesulfonamide (E30)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methyl- 376benzenesulfonamide (E31) 5-Chloro-N-[4-methoxy-3-(4-methylpipera- 402zin-1-yl)phenyl]-2-thiophenesulfonamide (E32)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naph- 412thalenesulfonamide (E33)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-naph- 412thalenesulfonamide (E34)5-(Dimethylamino)-N-[4-methoxy-3-(4-methylpipera- 455zin-1-yl)phenyl]-1-naphthalenesulfonamide (E35)4-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydro- 452/454benzofuran-5-yl]-benzenesulfonamide (E36)4-Methoxy-N-[4-methoxy-3-(4-methylpipera- 392zin-1-yl)phenyl]benzenesulfonamide (E37)4-n-Butyl-N-[4-methoxy-3-(4-methylpipera- 418zin-1-yl)phenyl]benzenesulfonamide (E38)4-Amino-N-[4-methoxy-3-(4-methylpipera- 377zin-1-yl)phenyl]-benzenesulfonamide (E39)2-Chloro-N-[4-methoxy-3-(4-methylpipera- 396zin-1-yl)phenyl]benzenesulfonamide (E40)3-Chloro-N-[4-methoxy-3-(4-methylpipera- 396zin-1-yl)phenyl]-benzenesulfonamide (E41)2,3,4-Trichloro-N-[4-methoxy-3-(4-methylpipera- 464/466zin-1-yl)phenyl]-benzenesulfonamide (E42)4-Chloro-N-[4-methoxy-3-(4-methylpipera- 424zin-1-yl)phenyl]-2,5-dimethyl-benzenesulfonamide (E43)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl- 376benzenesulfonamide (E44)2,5-Dibromo-3,6-difluoro-N-[4-methoxy-3-(4-methylpipera- 556zin-1-yl)phenyl]-benzenesulfonamide (E45)N-[4-Methoxy-3-(4-methylpipera- 418zin-1-yl)phenyl]-2,3,5,6-tetramethyl-benzenesulfona- mide (E46)5-Chloro-2-methoxy-N-[4-methoxy-3-(4-methylpipera- 426zin-1-yl)phenyl]-benzenesulfonamide (E47)3-Fluoro-N-[4-methoxy-3-(4-methylpipera- 380zin-1-yl)phenyl]benzenesulfonamide (E48)3,4-Difluoro-N-[4-methoxy-3-(4-methylpipera- 398zin-1-yl)phenyl]benzenesulfonamide (E49)4-Chloro-N-[4-methoxy-3-(4-methylpipera- 441zin-1-yl)phenyl]-3-nitro-benzenesulfonamide (E50)3-Chloro-N-[4-methoxy-3-(4-methylpipera- 410zin-1-yl)phenyl]-2-methyl-benzenesulfonamide (E51)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-8-quino- 413linesulfonamide (E52)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-phenyl- 438benzenesulfonamide (E53) 3,4-Dimethoxy-N-[4-methoxy-3-(4-methylpipera-374 zin-1-yl)phenyl]-benzenesulfonamide (E54)N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3,5-di- 381methyl-4-isoxazolesulfonamide (E55)4-Bromo-N-[4-methoxy-3-(4-ethylpipera- 454/456zin-1-yl)phenyl]benzenesulfonamide (E56)2,3-Dichloro-N-[4-methoxy-3-(4-methylpipera- 430zin-1-yl)phenyl]-benzenesulfonamide (E57)5-Iodo-N-[4-methoxy-3-(4-methylpipera- 502zin-1-yl)phenyl]-2-methylbenzenesulfonamide (E58)3-Iodo-N-[4-methoxy-3-(4-methylpipera- 488zin-1-yl)phenyl]benzenesulfonamide (E59)3-Iodo-N-[4-methoxy-3-(4-methylpipera- 502zin-1-yl)phenyl]-4-methylbenzenesulfonamide (E60)5-Chloronaphthalene-2-sulfonic acid[4-methoxy-3-(4-meth- 446ylpiperazin-1-yl)phenyl]amide (E61) 5-Chloronaphthalene-1-sulfonicacid[4-methoxy-3-(4-meth- 446 ylpiperazin-1-yl)phenyl]amide (E62)4-Chloronaphthalene-1-sulfonic acid[4-methoxy-3-(4-meth- 446ylpiperazin-1-yl)phenyl]amide (E63) 7-Chloronaphthalene-1-sulfonicacid[4-methoxy-3-(4-meth- 446 ylpiperazin-1-yl)phenyl]amide (E64)5-Chloro-2-methylbenzo[b]thiophene-3-sulfonic 466acid[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (E65)Benzofuran-2-sulfonic acid[4-methoxy-3-(4-methylpipera- 402zin-1-yl)phenyl]amide (E66) 1-Methyl-1H-indole-2-sulfonicacid[4-methoxy-3-(4-meth- 415 ylpiperazin-1-yl)phenyl]amide (E67)2,3-Dichloro-N-[4-methoxy-3-(4-methylpipera- 430/432zin-1-yl)phenyl]-benzenesulfonamide (E138)

Preparation of Aryl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamides

These compounds were prepared using one of the three general methods asoutlined below.

General Method 1

Examples 68-75 were prepared by the following general method from thecorresponding N-methyl piperazine analogues:

A solution of 1-chloroethylchloroformate (1.7 mmol) and the appropriateN-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-arylsulfonamide (0.34mmol) in 1,2-dichloroethane (4 ml) was refluxed for 0.75 h, cooled,diluted with diisopropylethylamine (1.7 mmol) and refluxed for a further2.5 hrs. The solution was concentrated to a residue which wasre-dissolved in methanol, refluxed for 1 hr and then stirred at roomtemperature for 24 h. The mixture was concentrated, and the residuepartitioned between ethyl acetate and aqueous sodium bicarbonatesolution. The organic layer was dried, concentrated to a residue andpurified by column chromatography on silica gel using amethanol/dichloromethane solvent gradient. The hydrochloride salt of theproduct was prepared by dissolving the pure material from chromatographyin acetone/dichloromethane and acidifying with ethereal HCl.

MS(MH⁺) 5-Pyridin-2-ylthiophene-2-sulfonic acid(4-methoxy-3-pipera- 431zin-1-ylphenyl)amide (E68) N-(4-methoxy-3-piperazin-1-ylphenyl-3-tri-416 fluoromethylbenzenesulfonamide (E69)3-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 474 sulfonamide(E70) 3,5-Dimethylisoxazole-4-sulfonic acid(4-methoxy-3-pipera- 367zin-1-ylphenyl)amide (E71)3,5-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 416/418sulfonamide (E72) 2,5-Dibromo-3,6-difluoro-N-(4-methoxy-3-pipera- 542zin-1-ylphenyl)benzenesulfonamide (E73) Naphthalene-1-sulfonicacid(4-methoxy-3-pipera- 398 zin-1-ylphenyl)amide (E74)2-Bromo-5-chlorothiophene-2-sulfonic acid(4-meth- 466/468oxy-3-piperazine-1-ylphenyl)amide (E75)

General Method 2

Examples 76-86 were prepared by the following general method from theappropriate N-Boc derivative (D4-D14):

A stirred solution of the appropriate N-Boc derivative (D4-D14) (10.3mmol) in methanol (100 ml) and 1M ethereal HCl (51.6 ml) was heated at60° C. for 1.5 h. The mixture was then concentrated and the residuestirred with acetone to afford the following title compounds as thehydrochloride salts.

MS(MH⁺) 2-Chloro-4-fluoro-N-(4-methoxy-3-piperazin-1-ylphenyl)ben-400/402 zenesulfonamide (E76)3-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 426/428 sulfonamide(E77) 3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 382/384sulfonamide (E78) 5-Chloronaphthalene-2-sulfonicacid(4-methoxy-3-pipera- 432/434 zin-1-ylphenyl)amide (E79)4-Bromo-5-chlorothiophene-2-sulfonic acid(4-meth- 466/468oxy-3-piperazin-1-ylphenyl)amide (E80) 2,5-Dichlorothiophene-3-sulfonicacid(4-methoxy-3-pipera- 422/424 zin-1-ylphenyl)amide (E81)4-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 426 sulfonamide(E82) 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid(4-meth- 452oxy-3-piperazin-1-ylphenyl)amide (E83)5-Chloro-2-methylbenzo[b]thiophene-3-sulfonic acid(4-meth- 452oxy-3-piperazin-1-ylphenyl)amide (E84) 1-Methyl-1H-indole-2-sulfonicacid(4-methoxy-3-pipera- 401 zin-1-ylphenyl)amide (E85)Benzofuran-2-sulfonic acid(4-methoxy-3-pipera- 388 zin-1-ylphenyl)amide(E86)

EXAMPLE 83 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid(4methoxy-3-piperazin-1-ylphenyl)amide hydrochloride (E83)

A stirred suspension of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonicacid(4-methoxy-3-(4-tert-butoxycarbonylpiperazin-1-yl)phenylamide (D10)(193 g) in tetrahydrofuran (820 ml) and concentrated hydrochloric acid(180 ml) was heated at reflux for 1.75 h after which time a solution wasobtained. The solution was concentrated and the residue dissolved in hotethanol (600 ml). Upon cooling, a solid precipitated which was filteredand recrystallised (ethanol/water 1:1) to give the title compound (E83)as a white solid, m.p. 276-280° C. (dec.) (142 g, 83%). δ_(H) (250 MHz,D6-dmso) 2.29 (3H, s), 2.90 (4H, br s), 3.01 (4H, br s), 3.55 (3H, s),6.54-6.71 (3H, m), 7.42 (1H, d, J8.8 Hz), 7.85 (1H, s), 7.93 (1H, d,J8.8 Hz), 9.03 (2H, br s), 10.3 (1H, br s). MH⁺ 452.

General Method 3

EXAMPLES 87-94 were prepared by the following general method:

A solution of the appropriate arylsulfonyl chloride (0.47 mmol) and theaniline from D16 (0.47 mmol) in dichloromethane (4 ml) and pyridine (2.4mmol) was stirred for 18 h at room temperature. The mixture was washedwith 1M aqueous HCl then water. The layers were separated and to theorganic one was added 4.4M aqueous KOH (1.4 mmol) with vigorous stirringfor 18 h. To the heterogeneous mixture was then added an equal volume of10% phosphate buffer. The layers were again separated and the organicphase was dried and diluted with 1M ethereal HCl to afford thehydrochloride salts of the following compounds as a precipitate.

MS(MH⁺) Naphthalene-2-sulfonic acid(4-methoxy-3-pipera- 398zin-1-ylphenyl)amide (E87) 5-Chloronaphthalene-1-sulfonicacid(4-methoxy-3-pipera- 432/434 zin-1-ylphenyl)amide (E88)4-Chloro-2,5-dimethyl-N-(4-methoxy-3-pipera- 410/412zin-1-ylphenyl)benzenesulfonamide (E89)3,4-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 416/418sulfonamide (E90) 3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-4-meth-396/398 yl-benzenesulfonamide (E91)2-Trifluoromethyl-N-(4-methoxy-3-pipera- 416zin-1-ylphenyl)benzenesulfonamide (E92)4-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 474 sulfonamide(E93) 4-tert-Butyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzene- 404sulfonamide (E94)

EXAMPLES 95-108

The dihydrobenzofuran derivative, below,

was prepared as described previously WO 95/11243 (Glaxo) and coupledwith the appropriate aryl sulfonyl chlorides in the manner described inExample 1 to afford the following compounds:

MS(MH⁺) Naphthalene-1-sulfonic acid[7-(4-methylpipera- 424zin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E95) Thiophene-2-sulfonicacid[7-(4-methylpiperazin-1-yl)-2,3-di- 380 hydrobenzofuran-5-yl]amide(E96) 5-Chlorothiophene-2-sulfonic acid[7-(4-methylpipera- 414/416zin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E97)5-Pyridin-2-ylthiophene-2-sulfonic acid[7-(4-methylpipera- 457zin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E98)2,5-Dichlorothiophene-3-sulfonic acid[7-(4-methylpipera- 448/450zin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E99)4-Bromo-5-chlorothiophene-2-sulfonic acid[7-(4-methyl- 492/494piperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E100)3-Bromo-5-chlorothiophene-2-sulfonic acid[7-(4-methyl- 492/494piperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E101)4-Chloro-2,5-dimethyl-N-[7-(4-methylpiperazin-1-yl)-2,3-di- 436hydrobenzofuran-5-yl]benzenesulfonamide (E102)5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic 478acid[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzo- furan-5-yl]amide(E103) Naphthalene-2-sulfonic acid[7-(4-methylpipera- 424zin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide (E104)3-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzo- 452/454furan-5-yl]benzenesulfonamide (E105)3,5-Dichloro-N-[7-(4-methylpiperazin-1-yl)-2,3-di- 442/444hydrobenzofuran-5-yl]benzenesulfonamide (E106)4-tert-Butyl-N-[7-(4-methylpiperazin-1-yl)-2,3-di- 430hydrobenzofuran-5-yl]benzenesulfonamide (E107)2,5-Dibromo-3,6-difluoro-N-[7-(4-methylpipera- 568zin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide (E108)

EXAMPLES 109-110

The following compounds were prepared from the corresponding N-methylanalogues by the general method described for Examples 68-75:

MS(MH⁺) 2,5-Dibromo-3,6-difluoro-N-(7-piperazin-1-yl-2,3-di- 554hydrobenzofuran-5-yl)benzenesulfonamide (E109)4-Chloro-2,5-dimethyl-N-(7-piperazin-1-yl-2,3-di- 422hydrobenzofuran-5-yl)benzenesulfonamide (E110)

EXAMPLE 111 5-Chloro-3-methylbenzo[b]thiophene-2-sulphonicacid[3-(4-cyclopropylmethyl-piperazin-1-yl)-4-methoxy-phenyl]amide(E111)

To a solution of 3-(4-benzyl-piperazin-1-yl)-4-methoxy-phenylamine (D22)(1 mmol) in acetone (5 ml) was added5-chloro-3-methylbenzothiophene-2-sulphonyl chloride (1 mmol). Stirringwas continued at room temperature for 14 hrs. The hydrochloride salt ofthe sulphonamide was collected by filtration, triturated with diethylether and dried in vacuo in 42% yield. Found MH⁺ 506/508.

EXAMPLE 112

5-Chloro-3-methylbenzo[b]thiophene-2-sulphonicacid[3-(4-benzyl-piperazin-1-yl)-4-methoxy-phenyl]-amide (E112)

The title compound was prepared in 32% yield using the procedureoutlined for E111. Found MH⁺ 542/544

EXAMPLE 113 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-hydroxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (E113)

To a suspension of boron tribromide dimethyl sulphide complex (620 mg, 2mmol) in 1,2 dichloroethane (30 ml) under argon was added5-chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]amide (E17) (0.2 mmol).The reaction mixture was heated to reflux for 12 hrs, cooled, quenchedby the addition of water (20 ml) and partitioned between saturatedaqueous sodium bicarbonate and dichloromethane. The organic phase wasdried over sodium sulphate and concentrated in vacuo. The residue waspurified by chromatography on silica gel to afford the title compound(E113). Found MH⁺ 452/454

General Method for the Preparation of Examples 114-116

A solution of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-hydroxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (E113) (10 mg,0.22 mmol) and 18-Crown-6 (58 mg, 0.22 mmol) in DMF (0.5 ml) was addedto potassium hydride (35% dispersion in mineral oil, 50 mg, 0.44 mol) atroom temperature under argon. After 10 minutes a solution of thealkylating agent (0.22 mmol) in DMF (0.3 ml) was added and stirring wascontinued for 12 hrs. The reaction mixture was quenched with water andthen concentrated in vacuo before partitioning between saturated aqueoussodium bicarbonate and dichloromethane. The organic phase was dried oversodium sulphate and concentrated in vacuo. The residue was purified bychromatography on silica to afford the following alkylated finalcompounds.

EXAMPLE 114 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-benzyloxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (E114)

Prepared in 22% yield using benzyl bromide. Found MH⁺ 542/544.

EXAMPLE 115 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-ethoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (E115)

Prepared in 28% yield using the procedure outlined above using ethyliodide. Found MH⁺ 480/482.

EXAMPLE 116 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-isopropoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (E116)

Prepared in 20% yield using the procedure outlined above using2-iodopropane. Found MH⁺ 494/496.

EXAMPLE 117 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonicacid[4-methoxy-3-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-amide (E117)

The title compound was prepared in 48% yield from D25 and5-chloro-3-methylbenzotiophene-2-sulphonyl chloride as described forE111. Found MH⁺ 467/469.

EXAMPLE 118 Naphthalene-2-sulfonicacid[2-bromo-5-(4-methylpiperazin-1-yl)phenyl]amide (E118)

The title compound (E118) was prepared from naphthalene-2-sulfonylchloride (100 mg, 0.44 mmol) and2-bromo-5-(4-methylpiperazin-1-yl)phenylamine (D27) (120 mg, 0.44 mmol)using the method of Example 1 (85 mg, 35%) MH⁺=460/462.

EXAMPLE 119 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-chloro-3-(4-methylpiperazin-1-yl)phenyl]amide (E119).

The title compound (E119) was prepared from4-chloro-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A,intermediate 42) (50 mg, 0.22 mmol) and5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (62 mg, 0.22mmol) using the method of Example 1 (49 mg, 44%) MH⁺=470/472.

EXAMPLE 120 Naphthalene-2-sulfonicacid[4-bromo-3-(4-methylpiperazin-1-yl)phenyl]amide (E120)

The title compound (E120) was prepared from4-bromo-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A, intermediate61) (600 mg, 2.23 mmol) and naphthalene-2-sulfonyl chloride (504 mg,2.23 mmol) using the method of Example 1 (939 mg, 92%) MH⁺=460/462.

EXAMPLE 121 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[3-(2-dimethylaminoethoxy)-4-iodophenyl]amide (E121)

The title compound was prepared from3-(2-dimethylaminoethoxy)-4-iodoaniline (WO95/15954, Description 50)(109 mg, 0.36 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonylchloride (100 mg, 0.36 mmol) using the method of Example 1 (70 mg, 36%)MH⁺=551/553.

EXAMPLE 122 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-yl]amide (E122)

The title compound (E122) was prepared from1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-ylamine (WO95/32967Description 4) (100 mg, 0.49 mmol) and5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (137 mg, 0.49mmol) using the method of Example 1 (40 g, 18%) MH⁺=450/452.

EXAMPLE 1231-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole(E123)

The title compound (E123) was prepared from6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (prepared from3-nitroaniline, using methodology of WO95/06637 Intermediate 3) (39 mg,0.18 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride(50 mg; 0.18 mmol) using the method of Example 1 (75 mg, 84%)MH⁺=462/464.

EXAMPLE 1241-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole(E124)

The title compound (E124) was prepared from5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (WO95/06637intermediate 3) (99 mg, 0.4 mmol) and5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (113 mg, 0.4mmol) using the method of Example 1 (194 mg, 92%) MH⁺=492/494.

EXAMPLE 125 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenyl]amide (E125)

The title compound (E125) was prepared from4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenylamine (D33) (58 mg,0.247 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride(70 mg, 0.247 mmol) using the method of Example 1 (103 mg, 81%).MH⁺=480/482.

EXAMPLE 126 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[2-(2-hydroxyethyl)-4-methoxy-3-(4-methylpiperazin-1-yl)phenyliamide(E126)

The title compound (E126) was prepared from2-[6-amino-3-methoxy-2-(4-methylpiperazin-1-yl)phenyl]ethanol (D32) (74mg, 0.28 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonylchloride (78 mg, 0.28 mmol) using the method of Example 1 (18 mg, 13%).MH⁺=510.

EXAMPLE 1271-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indolehydrochloride (E127)

A mixture of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[2-(2-hydroxyethyl)-4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide(E126) (218 mg, 0.25 mmol) and triphenyl phosphine (183 mg, 0.375 mmol)in dry THF (5 ml) under argon, was treated with a solution of diethylazodicarboxylate (110 mg, 0.375 mmol) in dry THF (5 ml). The mixture wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure, and the residue partitioned between dilutehydrochloric acid and ethyl acetate. The acidic layer was basified with40% sodium hydroxide and re-extracted with ethyl acetate. The organicphase was dried (Na₂SO₄) and evaporated under reduced pressure to givethe crude product, which was purified by chromatography on silica gel,eluting with methanol and dichloromethane and the hydrochloride salt wasformed (52 mg, 23%) MH⁺=492/494.

EXAMPLE 128 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amide (E128)

A solution of 3-methoxy-4-(4-methylpiperazin-1-yl)phenylamine (D35) (50mg, 0.23 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonylchloride (64 mg, 0.23 mmol) in dichloromethane (2 ml) was allowed tostand at room temperature overnight. The reaction mixture was dilutedwith dichloromethane and washed with potassium carbonate (aq), which wasback-extracted with further dichloromethane. The combined organic phaseswere dried (Na₂SO₄) and evaporated under reduced pressure to give acrude product, which was purified by chromatography on silica gel,eluting with methanol and dichloromethane. This gave the title compound(E128) as an off-white solid (36 mg, 34%) MH⁺=466.

EXAMPLE 1294-Bromo-N-[4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]benzenesulfonamide(E129)

The title compound (E129) was prepared from4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (freebase of D39) (107 mg; 0.49 mmol) and 4-bromobenzenesulfonylchloride (125mg, 0.49 mmol) using the method of Example 1 (179 mg, 77%) MH⁺=437/439.

EXAMPLE 130 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amide(E130)

The title compound (E130) was prepared from4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (freebase of D39) (100 mg, 0.46 mmol) and5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (129 mg, 0.46mmol) using the method of Example 1 (177 mg, 77%). MH⁺=463/465.

EXAMPLE 131 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-3-(1-methylpiperidin-4-yl)phenyl]amide (E131)

The title compound (E131) was prepared from4-methoxy-3-(1-methylpiperidin-1-yl)phenylamine (D38) (150 mg, 0.68mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (192mg, 0.68 mmol) using the method of Example 1 (108 mg, 32%) MH⁺=465/467.

EXAMPLE 132 Naphthalene-2-sulfonicacid[3-(4-methylpiperazin-1-yl)phenyl]amide (E132)

The title compound (E132) was prepared from3-(4-methylpiperazin-1-yl)benzenamine and naphthalene-2-sulfonylchloride according to the method of Example 1 MH⁺=382.

Preparation of aryl-N-(4-methoxy-3-piperazin-1-yl)-benzenesulfonamideHydrochlorides on Solid Phase EXAMPLES 133-137

The resin from Description 42 was stirred for 24 h at room temperaturewith a solution of 1-chloroethylchloroformate (1.1 mmol) indichloromethane (2 ml) then filtered and washed with dichloromethane.The filtrate was concentrated and the residue redissolved in methanol (3ml) and the solution refluxed for 5 h. The solution was thenconcentrated to yield the title compound.

The following compounds were prepared as described above:

compound MH⁺ 2,3,4-Trichloro-N-(4-methoxy-3-piperazin-1-yl- 450/452phenyl)benzenesulfonamide (E133)2,3-Dichloro-N-(4-methoxy-3-piperazin-1-yl-phenyl) 416/418benzenesulfonamide (E134)3-Chloro-2-methyl-N-(4-methoxy-3-piperazin-1-yl-phenyl) 396/398benzenesulfonamide (E135) 4-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)382/384 benzenesulfonamide (E136) 5-Bromo-thiophene-2-sulfonic acid(4-methoxy-3-piperazin- 432/434 1-yl-phenyl)-amide (E137)

EXAMPLE 1382,3-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide(E138) MS(MH⁺) 430/432 was Prepared According to the General Method ofExample 1 EXAMPLES 139-141

The following compounds were prepared in an analagous way to Examples68-75

MS(MH+) 1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5- 524/526phenyl-6-piperazin-1-yl-2,3-dihydro-1H-indole (E139)5-Chloro-1-(5-chloro-3-methylbenzo[b]thiophene-2- 482/484sulfonyl)-6-piperazin-1-yl-2,3-dihydro-1H-indole (E140)1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-7- 462/464piperazin-yl-1,2,3,4-tetrahydroquinoline (E141)

EXAMPLE 142 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methyl-3-(4-methylpiperazin-1-yl)phenyl]amide (E142)

The title compound (E142) was prepared from5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride and4-methyl-3-(4-methylpiperazin-1-yl)benzenamine according to the methodof Example 1 MH⁺=448/450.

EXAMPLE 143 (S)-5-Chloro-3-methylbenzo[b]thiophene-2-sulfonicacid[4-methoxy-3-(1-methylpyrrolidin-2-ylmethoxy)phenyl]amide (E143)

A solution of (S)-1-methyl-2-(2-methoxy-5-aminophenoxy)pyrrolidine (D44)(0.22 g;9.3×10⁻⁴ mol) in DCM (10 ml) containing DIPEA (0.162 ml;9.3×10⁻⁴mol) was treated with 5-chloro-3-methylbenzene-2-sulphonyl chloride(0.262;9.3×10⁻⁴ mol) portionwise. Stirred at RT for 18 h, thenevaporated in vacuo and the residue purified by Sep-Pak Silica-gelcolumn chromatography with 2% MeOH/DCM as eluent to yield the titlecompound as a clear, colourless gum (0.14 g; 31%). This was converted tothe hydrochloride salt with HCl in Et2O (0.31 ml of a 1.0M solution)with trituration yielding the title compound (E143) as the salt as awhite, crystalline solid (0.13 g) MH⁺=481/483.

Method for assay of 5-HT6 antagonistic activity:

The test compounds were dissolved in polyethylene glycol:dimethylsulphoxide (1:1) at 1 or 10 mM and diluted to 0.1 mM using 5 mM trisbuffer (pH 7.7@25° C.). Dissolution was assisted by addition of 0.02 ml5M HCl plus heating to 40° C. and sonication for 10 minutes. Serialdilutions of drugs in the same buffer were carried out using either aTECAN 5052 or Biomek 2000 Workstation. Samples of the diluted testcompounds (0.05 ml) were mixed with 0.05 ml of radio-ligand [³H]-LSDprepared in the incubation buffer, and 0.4 ml of a suspension of apreparation of the washed membranes of HeLa_(—)5HT6 cells (acquired fromDr. D. Sibley, NIH, Bethesda, see Ref 1)(see Table 1), also in theincubation buffer. The details of the incubation conditions for eachassay are shown in Table 2. The incubation buffer was 50 mM Trizma(Sigma, UK) pH 7.7@25° C., 4 mM MgCl₂.

After incubation at 37° C., the mixtures were filtered using a PackardFiltermate in Packard TopCount format. Filters were washed with 4×1 mlaliquots of ice-cold incubation buffer. Filters were dried andimpregnated with 0.04 ml of Microscint 20 (Packard). IC₅₀ values wereestimated from the counts per minute using a four parameter logisticcurve fit within EXCEL (2). K_(i) values were calculated using themethod of Cheng and Prusoff (3). pIC₅₀ and pK_(i) are the negative log10of the molar IC₅₀ and K_(i) respectively.

TABLE 1 Details of the methods used to prepare membranes for bindingassays 1st spin/ Incubation protein conc. cells/ml resuspensionresuspension before final in stored in stored cells/ml 1, 2, 3 spinaliquots aliquots 7 × 10⁷ Yes 20 min at 37° C. 4 mg/ml 1.0 × 10⁸

TABLE 2 Summary of receptor binding assay conditions proteinradio-ligand (ug/ [³H]-LSD Specific Activity Non-Specific sample) (nM)(Ci/mmol) Definition Kd (nM) 40 2.0 83 Methiothepin 3.1

References

1. MONSMA, F. J., SHEN, Y., WARD, R. P., HAMBLIN, M. W., SIBLEY, D. R.1993. Cloning and expression of a novel serotonin receptor with highaffinity for tricyclic psychotropic drugs. Mol. Pharmacol., 43, 320-327.

2. BOWEN, W. P., JERMAN, J. C. 1995. Nonlinear regression usingspreadsheets. Trends in Pharmacol. Sci., 16,413-417.

3. CHENG, Y. C., PRUSSOF, W. H. 1973. Relationship between inhibitionconstant (Ki) and the concentration of inhibitor which causes 50%inhibition (IC50) of an enzymatic reaction. Biochem. Pharmacol, 92,881-894.

The compounds of Examples 11, 15, 17, 61, 65, 70, 72, 77, 78, 79, 83,84, 87 and 90 all showed particularly good selective 5-HT6 receptorantagonist activity, having pKi values above 8.0 at human cloned 5-HT6receptors.

What is claimed is:
 1. A method of enhancing cognitive memory comprisingadministering a safe and effective amount of a compound of

wherein: P is benzothiophene, benzothiadiazole, quinoline, benzofuran orindole; A is a single bond, a C₁₋₆alkylene or a C₂₋₆alkenylene group; R¹is halogen, C₁₋₆alkyl optionally substituted by one or more halogenatoms, C₃₋₆cycloalkyl, COC₁₋₆alkyl, C₁₋₆alkoxy, OCF₃, hydroxy,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, amino,C₁₋₆alkylamino or C₁₋₆dialkylamino, cyano or R¹ is phenyl, naphthyl; nis 0, 1, 2, 3, 4, 5 or 6: R² is hydrogen, C₁₋₆ alkyl or aryl C₁₋₆ alkylor R² is linked to R³ to form a group (CH₂)₂ or CH₂)₃; R³ is a group R⁵or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃O or R³ is linked toform a group (CH₂)₂ or (CH₂)₃; R⁴ is an N-piperazine ring optionallysubstituted by C₁₋₆alkyl; and R⁵ is hydrogen, halogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, COC₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, hydroxyC₁₋₆alkyl,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, trifluoromethyl, cyanoor aryl.